Enhanced sampling without borders: on global biasing functions and how to reweight them

Molecular dynamics (MD) simulations are a powerful tool to follow the time evolution of biomolecular motions in atomistic resolution. However, the high computational demand of these simulations limits the timescales of motions that can be observed. To resolve this issue, so called enhanced sampling techniques are developed, which extend conventional MD algorithms to speed up the simulation process. Here, we focus on techniques that apply global biasing functions. We provide a broad overview of established enhanced sampling methods and promising new advances. As the ultimate goal is to retrieve unbiased information from biased ensembles, we also discuss benefits and limitations of common reweighting schemes. In addition to concisely summarizing critical assumptions and implications, we highlight the general application opportunities as well as uncertainties of global enhanced sampling.